We recently reported a model of chronic bleomycin pulmonary toxicity in mice, using lung hydroxyproline levels as an index of fibrosis, and correlating increases in lung collagen content with four morphometric parameters of lung injury by light microscopy. We have also developed a high-pressure, liquid chromatographic assay to separate bleomycins and their desamino-metabolites, and are investigating bleomycin metabolism by bleomycin hydrolase in lung and other tissues. These techniques, as well as tissue culture and therapy of transplantable murine tumors, will be applied to the study of bleomycin's therapeutic and toxic effects, as follows: 1. Since oxygen is essential for bleomycin-induced DNA scission to occur in vitro, possibly mediated by superoxide and hydroxyl free radicals, hypoxic-sensitizing agents such as misonidazole may selectively increase the anti-tumor activity of bleomycin without affecting lung toxicity. The role of oxygen will be studied in L1210 leukemia cell culture, and by measuring lipid peroxidation in whole lung and its subcellular fractions. 2. Some antineoplastic drugs used in combination with bleomycin may potentiate its pulmonary toxicity, and these deleterious drug interactions may be identified by combination toxicity studies in the mouse model. Potentially beneficial interactions with antioxidants, inhibitors of collagen synthesis, or anti-inflammatory agents will also be investigated. 3. Bleomycin hydrolase activity will be measured in several murine tumors, in human cancer surgical specimens, and in lung tissues when available. The importance of bleomycin metabolism in determining tumor sensitivity and toxicity will be examined. Ultimately, this may enable us to predict responsiveness to bleomycin therapy in individual patients, and lead to methods for identifying patients at greater risk for developing pulmonary toxicity. These studies should enhance our understanding of the mechanisms of activity of bleomycin, and lead to more rational use of this drug.